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Research ArticleFormulation and Development of a ValidatedUV-Spectrophotometric Analytical Method of Rutin Tablet

Murad N. Abualhasan,1 JumanaMansour,1 Nidal Jaradat,1

Abdel Naser Zaid,1 and Ibrahim Khadra2

1Department of Pharmacy, Faculty ofMedicine&Health Sciences, An-NajahNational University, P.O. Box 7, Nablus, State of Palestine2Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK

Correspondence should be addressed to Murad N. Abualhasan; m [email protected]

Received 4 February 2017; Revised 20 March 2017; Accepted 29 March 2017; Published 16 May 2017

Academic Editor: Josep Esteve-Romero

Copyright © 2017 Murad N. Abualhasan et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Rutin is available in some foods, fruits, and vegetables. It has various beneficial medical effects making it useful in the treatment ofvarious diseases. Rutin is available in different oral dosage forms such as tablets or capsules, widely available in themarket. Rutin andmany herbal medicines lack quality control due to unavailability of analytical methods. In this study, we formulated rutin tablet andstudied its stability using a simple developed analytical method.The dissolution profile of our formulated tablet was also inspected.The results showed that our developed method was linear (𝑅2 = 0.999), precise (% RSD = 0.026), and accurate (% recovery =98.55–103.34). The formulated rutin tablet was stable under accelerated conditions as well as room temperature for 150 days (%assay > 91.69). The dissolution profile over 45 minutes of our formulated tablet showed a better dissolution (26.5%) comparedwith the internationally marketed Rutin� tablet (18.5%). This study can serve as a guideline to companies that manufacture herbalproducts to improve their formulated herbs and apply validated analytical methods to check the quality of their product.

1. Introduction

Rutin is 3,3,4,5,7-pentahydroxy flavones-3-rutinoside. Itis the yellow crystalline rhamnoglucoside of the flavonoidquercetin and has a chemical formula C

27H30O16with chem-

ical structure as shown in Figure 1.Rutin is slightly soluble in water and has a higher

solubility in organic solvent such as methanol. It showedlow bioavailability after studying it in animals and humanvolunteers, due to its low water solubility [1].

Rutin is found in some foods, fruits, vegetables, and plant-based beverages such as buckwheat, onions, apples, berries,orange, grape fruit, lemon, tea, and asparagus. Rutin hasvarious beneficialmedical effects: it possesses antioxidant andanti-inflammatory effects and is widely used for hemorrhageand varicose [2, 3].

Various dosage forms are available in the local andinternational market such as tablets and capsules and intopical applications such as gels. Rutin is available in these

dosage forms either alone or in combination with otheractive ingredients. Liquid chromatography and UV spec-trophotometer methods are the most popular methods ofrutin analysis [4, 5]. Tablets are the mostly used dosageforms available in themarket. Formulations of tablets includediluents, binders, and disintegrants. The selection of theseexcipients should take into consideration the physical andchemical properties which include compatibility, flowability,solubility, hygroscopicity, lubricity, and its effect on stabilityof the tablet [6–10].

Employment of a fully validated analytical method ishighly needed to quantify rutin in various dosages. The typi-cal validation parameters should be considered in the analyt-ical validation procedure; these parameters include accuracy,precision, repeatability, intermediate precision, specificity,detection limit, quantitation limit, linearity, and range [11–15]. The ICH guidelines clearly stated the requirement andestablishment of stability-indicating assaymethod. It requiresthe conduct of forced decomposition studies under a variety

HindawiInternational Scholarly Research NoticesVolume 2017, Article ID 2624947, 7 pageshttps://doi.org/10.1155/2017/2624947

https://doi.org/10.1155/2017/2624947

2 International Scholarly Research Notices

1

2

3

4

5

6

7

8 O

O

OOO

O

A

B

C

HO

HO

HO

OH

OH

OHOH

OH

OH

OH

CH3

3�㰀

2�㰀

6�㰀

1�㰀

4�㰀

5�㰀

Figure 1: Chemical structure of rutin.

of conditions, like pH, light, oxidation, and dry heat.Thedrugmust be separated from the degradation products and themethod must be able to analyze each individual degradationproduct [16, 17].

To our knowledge, there is no pharmacopeial method orany validated method that quantifies rutin in its final dosageform.The objective of this study is to formulate a rutin tabletand compare its quality (mainly tablet dissolution) with whatis available in the local and internationalmarket using a homedevelopedmethod.Themethodwill be validated according tothe international standards [18, 19]. The developed analyticalmethod will be applied in quantification of rutin in bothraw material and its final tablet dosage form. The dissolutionof our developed tablet formulation will be evaluated andwill be compared to the dissolution of other rutin tabletsthat are available in the market. Moreover, a stability studyunder normal and stress conditions will be conducted forour formulated tablet [20]. Our validated methods can beincluded in one of the international pharmacopeia.Moreover,the quality R&D and quality control lab sections of the herbalindustry can benefit from this research project to improvetheir herbal products and control its quality.

2. Materials and Methods

2.1. Materials. All reagents used in this study had the min-imum requirements set by American Society for TestingMaterial (ASTM) and American Chemical Society (ACS)specifications for analytical reagents. All the chemicals usedwere purchased from reliable sources; these chemicals andmaterials include the following: acetone, acetonitrile, ethanol,and potassium dihydrogen phosphate were purchased fromSigma Aldrich, St. Louis, USA. Hydrochloric acid 32%,hydrogen peroxide 30%, isopropyl alcohol, methanol, andtetrahydrofuranwere purchased fromThermo Fisher GmbH,Karlsruhe, Germany.

Rutin trihydrate powder 99% was purchased from SigmaAldrich, St. Louis, USA. All tablet excipients were givenas a gift from the Jerusalem Pharmaceutical Company, andthese excipients include aerosil, acdisol, magnesium stearate,and microcrystalline cellulose (MCC). Rutin tablet (Solgar-Leonia, New Jersey, USA) was purchased from a local com-munity pharmacy shop and was used as a market reference.

2.2. Instrumentation. The instruments that were used duringour research include the following: disintegration testers(Erweka, Model-ZT 220, Germany), UV/visible spectropho-tometer (JENWAY, Model-7315, Staffordshire, UK), PaddleDissolution Tester (HSIANGTAI, Model-DT-6), pH meter(JENWAY, Model-3510 Staffordshire, UK), hotplate stirrer(LabTech Model-ES35A, Hopkinton, USA), analytical bal-ance (Nevada Weighing, Model-220), and multicheck ofhardness, thickness, and diameter (Erweka, Model-5.1, Ger-many), oven (BINDER,Model-ED56, Germany), and rotava-por (Heidolph, Model-VV2000, Schwabach, Germany).

2.3. Analytical Method Development

2.3.1. Determination of Wavelength of Maximum Absorption(𝜆max) of Rutin. Rutin (0.1mg/ml) was dissolved in solventdiluent (methanol : water; 9 : 1) and the UV-Vis spectrum ofrutin trihydrate was tested using UV spectrophotometer inthe range of 200–800 nm. The interfering effect of excipientson the maximum absorption (𝜆max) was tested by scanningthe spectrumof each excipient alone aswell as in combinationwith rutin.

2.3.2. Determination of Rutin Hydrochloride in Bulk. Thedevelopedmethodwas applied to determine rutin in bulk. Anaccurate weight (10mg) of rutin bulkmaterial was transferredinto a 100ml volumetric flask containing 20ml of diluent andthe volume was made up to the mark using the same diluent.Appropriate volume 40ml of this solution was transferredto a 100ml volumetric flask, and the volume was adjustedto the mark using diluent. The absorption was recorded at360 nm and the concentrations of the drug were calculatedfrom linear regression equations.The % recovery and % RSDof the rutin in bulk were calculated for 5 repeated tests.

2.3.3. Analysis of Formulated and Commercial Tablet Formu-lation. The developed method was also applied to determinerutin in tablets. An average weight of rutin tablet was taken ina 250ml volumetric flask and the volume was made up to themark with diluent. From this, 4ml was taken and transferredto a 100ml volumetric flask and the volume was made up tothe mark with diluent to give 0.04mg/ml concentration. Theabsorption was recorded at 360 nm and the concentrations ofthe drug were calculated from the linear regression equation.The% assay and % RSD of the rutin in tablets were calculatedfor 5 repeated tests.

2.4. Analytical Method Validation. The linearity and rangeof the developed method were performed by measuringthe absorption of a series of rutin standard solutions(0.009–0.09mg/ml) at 𝜆max of 360 nm. The absorptions ofthese standard solutions were plotted against their concen-tration. The regression line equation and the square of thecorrelation coefficient (𝑅2) were calculated.

The accuracy and precision validation parameters wereevaluated by testing three concentrations (80%, 100%, and120%) of the rutin theoretical value, and three replicates ofeach concentration were tested.

International Scholarly Research Notices 3

Table 1: Compositions of formulated tablets.

Component Formula (F1) Formula (F2) Formula (F3)Rutin 250 250 250MCC 182 180 185Magnesium stearate 5 5 5Aerosil 5 5 5Acdisol 8 10 5Total weight 450 450 450

The recovery and precision were performed by test-ing three prepared working solutions that are equivalentto 80, 100, and 125% of the test concentration. Triplicatemeasurements were done for each prepared solution. Themeasurements were repeated for three consecutive days. Thepercentage recovery and % RSD were then calculated.

The selectivity of the method was carried out by mea-suring the absorbance of the excipients mixture without theactive ingredient. The absorbance was measured in the rangeof 200–800 nm.The resulting spectrum of the excipients wascompared to that of rutin and was checked for any interfer-ence at measuring 𝜆max of 360 nm. The method specificityand selectivity were also checked for any interference ofdegradative substances. This was performed by subjectingthe sample solution to forced degradation conditions. Forceddegradation was carried out by exposing the formulationsolution (0.04mg/ml) to four stress conditions, 0.1 N HCl,0.1 N NaOH, 0.3% H

2O2, and UV light at 254 nm for 3 hrs.

Moreover, the rutin formulated tablets were subjected to hightemperature (40∘C) for 150 days.

The robustness of the method was performed by examin-ing the effect of slight changes on absorption at wavelengths360 ± 2, the effect of slight changes in diluents composition inthe ratio of methanol : water; 9 : 2, andmethanol : water; 10 : 1,was also examined.The effect of changing personnel has beenstudied by using another analyst.

The LOD and LOQ of the method were calculated basedon the standard deviation of the response (𝜎) and slopeapproach as defined in ICH guidelines [21]. LOD and LOQwere calculated according to 3.3 ∗ 𝜎/Slope for LOD and10 ∗ 𝜎/Slope for LOQ.2.5. Tablet Formulation Development. Three different formu-lae of Rutin 250mg tablets were prepared in our researchlab. The components used are rutin trihydrate, magne-sium stearate, microcrystalline cellulose (MCC), aerosil, andacdisol.The detailed composition of the three tablet formula-tions are listed in Table 1.The tablets were prepared by “directcompression” method [9], according to the flowchart shownin Figure 2.

2.6. Dissolution Profile of Formulated Rutin Tablet. Dissolu-tion was done according to USP and ICH guidelines [22, 23].The dissolution was done using USP apparatus 2 (paddle).The dissolution test was performed in three different pHmedia of 1.2 (0.1 N HCl), 4.5, and 6.8 phosphate bufferprepared according to USP. The dissolution apparatus was

Weighing

Sifting

Mixing:(1)(2) Glidant(3) Lubricant

CompressionAPI + filler/binder + disintegrant

Figure 2: Steps of formulation preparation.

run at 50 rpm and 37∘C for 45 minutes. One tablet was placedinto each of the six dissolution vessels containing 900ml ofdissolution medium. 10ml of the sample was withdrawn bysyringes from each dissolution vessel at time intervals of 5, 10,15, 20, 25, 30, 35, 40, and 45 minutes. The average reading oftriplicatemeasurements was taken to calculate the percentageof dissolved rutin using the following formula:

% of dissolved Rutin

= Actual amount of released rutinTheoretical amount of rutin in tablet

∗ 100. (1)

The dissolution profiles of the formulated tablets and themarketed rutin tablet were studied in the selected dissolutionmedia. Comparison of dissolution was based on the values ofthe calculated similarity factor (𝑓

2) and dissimilarity factor

(𝑓1) of the dissolution profile for the formulated and mar-

keted rutin tablets. Values for𝑓1and𝑓2were calculated using

(2) and (3), respectively.The 𝑓2factor measures the closeness

between two profiles and𝑓1measures difference between two

profiles. 𝑅𝑡and 𝑇

𝑡in equations represent the percentages of

drug dissolved at each time point for the reference (markettablet) and test (formulated tablet), respectively. An 𝑓

1value

greater than 15 indicates significant dissimilarity, and an 𝑓2

value greater than 50 indicates significant similarity [24–26]:

𝑓1= {[∑𝑛𝑡=1 𝑅𝑡 − 𝑇𝑡][∑𝑛

𝑡=1𝑅𝑡] } × 100, (2)

𝑓2= 50 ⋅ log{[1 + 1𝑛

𝑛∑𝑡=1

(𝑅𝑡− 𝑇𝑡)2]−0.5 × 100} . (3)

2.7. Weight Variation and Content Uniformity of the Formu-lated Tablets. Weight variation of the formulated tablets wasperformed in accordance with the USP method specified foruncoated tablets [19].

The weight variation is done by weighing 20 tabletsindividually and the test will be considered successful if itmeets the requirements set by the official pharmacopeia.

The content uniformity test was done in accordance withUSP. The rutin content for each tablet was calculated relativeto the label claim.


Table 2: Recovery and intraday precision assay of home prepared formula of rutin 250mg tablet.

DayRutin (mg/ml)

% RSD ANOVA % recoverySample number1 2 3

80%1 0.0317 0.0317 0.0313 0.026

0.6398.55 ± 0.7

2 0.0317 0.0313 0.0317 0.026 98.55 ± 0.73 0.0317 0.0320 0.0320 0.026 99.73 ± 0.7

100%1 0.0415 0.0415 0.0415 0.000

0.11103.65 ± 0

2 0.0411 0.0407 0.0407 0.020 102.08 ± 0.53 0.0415 0.0411 0.0415 0.020 103.34 ± 0.5

125%1 0.0509 0.0509 0.0505 0.016

0.178101.52 ± 0.4

2 0.0513 0.0513 0.0509 0.016 102.27 ± 0.43 0.0509 0.0513 0.0509 0.016 102.02 ± 0.4

2.8. The Physical Specification. The disintegration time ofour formulated tablet was performed according to USP [27].When all the tablets have been completely disintegrated, thiswas recorded as disintegration time.

Tablet physical specifications like the hardness, thickness,and diameter were determined and tested using multicheck(Erweka 5.1). The test was done on ten tablets; the averagereading was assigned as the tablet hardness, thickness, anddiameter specifications of the formulated tablets.

2.9. Stability of Formulated Rutin Tablet. The stability of theformulated rutin tablet was studied by storing the tablet atroom temperature as well as at 40∘C and analyzed period-ically by using the developed analytical test method. Thepercentage content of formulated rutin tablets was calculatedperiodically through 150 days.

3. Results

3.1. Analytical Method Development. The spectrum of rutinsolution in the range of 200–800 nm showed two absorptionmaxima, at 360 nm and at 260 nm. The results also demon-strated no interference of the excipient used in formulationat the measuring absorption maxima (Figure 3).

The developed method was applied to determine rutin inbulk and tablets. The % amount of bulk rutin recovered wasbetween 98.92% and 100.33% and the % RDS was 1.22. The %assay of rutin tablets was between 98.24% and 101.31% and theRSD was 1.32.

3.2. Analytical Method Validation Results. The absorption ofserial standard solutions in the range of 0.009–0.09mg/mlwas plotted against its concentration and the regression linewas examined for linearity over the concentration range. Thecurve was linear with a regression line equation of 𝑦 =25.035𝑥 + 0.0634. The goodness-of-fit (𝑅2) was also foundto be 0.999 indicating a linear relationship in the mentionedrange.

10

9

8

7

6

5

4

3

2

1

0

0 100 200 300 400 500 600

Exepient

Figure 3: Spectrum of rutin and excipients in the range of200–800 nm.

The accuracy and precision of the method were estab-lished on the results of three concentration levels aroundconcentration test value of rutin (80%, 100%, and 120%). Theresults of the recovery of rutin active ingredient showed agood accuracy (98.55–103.34).

The prepared solutions were tested for precision in threereplicates and an intraday testing for three consecutive days(intermediate precision).The results indicate that themethodis precise; the % RSD for the intraday was in the acceptablerange (0.016–0.026) and 𝑃 value of the ANOVA results(intermediate precision) was >0.05 (Table 2).

The results stability-indicating study of formulated rutintablet under stress conditions of 0.1 N NaOH, 0.1 N HCl, UVlight (254 nm), and 0.3% H

2O2showed that rutin tablets are

only stable in the UV light and slightly degraded in the H2O2

as the percentage assay has dropped from 104% to about80%. The results also demonstrate that instant degradationhas occurred on the tablet after the addition of alkaline andacidic solution, and the assay dropped to about 60%.


0

5

10

15

20

25

30

0 10 20 30 40 50

Formula 1Formula 2

Formula 3

−5

Figure 4:Dissolution profile of three formulations in the dissolutionmedia (pH 6.8).

3.3. Weight Variation and Content Uniformity of Rutin Tablet.Weight variationwas performed according toUSP; the resultsshow that the variation for any of tested tablets was not morethan 2.6% from the mean weight.

Theuniformity content test was also performed accordingto the USP; the results show that % RSD value of the assayedtablets was 1.05 and no tablet % assay was out of the limit(85–115%).

3.4. Dissolution Profile. The dissolution profile was done tocompare in vitro dissolution profiles of different rutin tabletformulation. The results clearly demonstrate that formula 1(F1) has the best dissolution among three formulations.Thus,we selected formula 1 (F1) for the shelf life, accelerated, andstress stability studies (Figure 4).

The results also show amoderate dissolution (26.7%) after45 minutes, but it reaches a plateau after approximately 20minutes. The low dissolution of the tablet was due to the lowsolubility of rutin in aqueous media.

In order to test the dissolution profile of the other dissolu-tionmedia, F1 was tested in three different dissolutionmedia,namely, phosphate buffer 6.8, phosphate buffer 4.5, and 0.1 NHCl; the dissolution was not significantly different betweenthe three media (𝑃 < 0.05). Furthermore, the dissolutionfor the formulated rutin tablet (F1) and for marketed rutintablet was tested using phosphate buffer of pH 6.8.The results(Figure 5) show slightly higher dissolution for our formulatedtablet compared to the rutin tablet.

3.5. The Physical Specification. Some of the physical parame-ters of our formulated tablet including disintegration, hard-ness, thickness, and diameter were determined as tabletspecification.

The disintegration of the tablet was performed using USPspecified disintegration apparatus. The tablets were placed inthe specified baskets and observed for complete disintegra-tion. The formulated tablets were seen to disintegrate totallyafter 4 minutes.

The tablets were tested for their hardness, thickness, anddiameter simultaneously using Erweka multicheck instru-ment. The average value of the tested parameters will be

0

5

10

15

20

25

30

0 10 20 30 40 50

Comercial tabletFromulated tablet

−5

Figure 5: Dissolution profile for formulated rutin and commercialrutin tablet at phosphate buffer media (pH = 6.8).

Table 3: Hardness, diameter, and thickness of the formulated tablet.

Tablet specification Average Minimum MaximumWeight (mg) 445.4 440.7 450.9Thickness (mm) 2.31 2.29 2.35Hardness (N) 253 227 284Diameter (mm) 13.03 12.99 13.09

Table 4: Stability of tablets at room temperature and 40∘C.

Day Tablet stored 40∘C

(% assay )Tablet stored at roomtemperature (% assay)

7 96.38 106.4114 95.98 103.58150 91.69 96.33

considered as our tablet specification. Table 3 shows thedetailed data of the tested parameters.

3.6. Stability of Formulated Rutin Tablet. To study the tablet’sstability, the formulated tablets were stored in room tempera-ture at 40∘C andwere analyzed periodically through 150 days.The results indicate the tablets and the tablet assay after 150days at room temperature and 40∘C were 96.33 and 91.69,respectively (Table 4).

4. Discussions

The spectrum shows two absorption maxima, at 360 nm andat 260 nm. The absorption at 260 nm was linear with an𝑅2 almost similar to 360 nm. However, we adapted 360 nmas a measuring wavelength in our analytical method toavoid any absorption from the excipient and degradationproduct. To examine absorptivity of the excipients on the


measuring 𝜆max 360 nm, all the expected excipients whichwere included in formulation were dissolved in the diluentsand their absorbance wasmeasured.The results show that theabsorbance at the selected 𝜆max is negligible relative to rutinabsorption at 𝜆max 360 nm. The result clearly demonstratesthat there is no interaction between the excipients and rutinactive ingredient and thewavelength is selective for rutin.Thespecificity and selectivity of the developed analytical methodwere also tested by stability-indicating study. The formulatedrutin tablet was put under different stress conditions: 0.1 NNaOH, 0.1 N HCl, UV light (254 nm), and 0.3% H

2O2. The

results showed that method can selectively quantify any dropin the assay of rutin in the formulated tablets under the aboveselected stress conditions.

The results clearly demonstrate that our formulatedtablets comply with weight variation and the content unifor-mity; according to USP, weight variation test will pass onlyif not more than two of the individual weights deviate fromthe average weight by ±7.5% and none deviates by more thantwice that percentage. Our results show that the variation forany of the tested tablets was not more than 2.6% from themean weight. The uniformity content according to the USPwill pass if the relative standard deviation (% RSD) is ≤15 andno % assay value is outside 85–115%. The test fails if one ormore values are outside 75–125%.The uniformity content testresults showed that RSDvalue of the assayed tablets was 1.05%and no tablet has % assay that was out of the limit (85–115%).The rutin dissolution profile of the formulated tablet showeda slight dissolution improvement over the marketed rutintablet. However, the result of similarity factor (f2) was >50and the dissolution data revealed that there was no statisticaldifference (𝑃 > 0.05) between the formulated tablet and themarketed one.

The developed analytical method showed good linearity,accuracy, precision, and specificity. This study recommendsa simple, validated analytical method for herbal and foodsupplement manufacturers to use in quality control of theirproducts.

5. Conclusion

In this study, we developed a tablet formulation of rutin250mg in our research labs, and we also developed a simplevalidated UVmethod for analysis and quantification of rutinin formulated tablets as well as raw material. The dissolutionprofile of our formulated tablet was slightly more than themarketed rutin tablet.The shelf and accelerated stability studyresults of the formulated tablet showed that the formulatedtablets are stable. This study can guide companies thatmanufacture herbal products to improve their formulatedherbals and apply validated analytical methods to check theirproduct quality.

Conflicts of Interest

The authors declare that they have no competing interests.

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Formulation and Development of a Validated UV ...downloads.hindawi.com/archive/2017/2624947.pdf4...

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